The need for an efficacious vaccine to reduce malaria morbidity and mortality due to Plasmodium falciparum is widely recognized and urgent. For malaria endemic areas, such a vaccine must target blood- stage parasites. Presently, the most viable approach is to immunize with subunit vaccines to induce antibodies that neutralize extracellular merozoites and prevent the invasion of host erythrocytes. P. falciparum merozoite surface protein -1 is considered the prime candidate for inclusion in such a vaccine and supporting data are substantial. Thus far, the inability to induce high titer of neutralizing antibodies upon immunization of human subjects with PfMSP-1 based subunit vaccine has impeded the effort. Recognizing that alternate and redundant pathways of merozoite invasion exist, it is also very unlikely that immunization with PfMSP-1 alone will be adequate. Working in the Plasmodium yoelii rodent model, we have shown that merozoite surface protein-8 is a target of neutralizing antibodies and can be used to enhance the immunogenicity and efficacy of MSP-1 based vaccines. Our hypothesis is that fusion of P. falciparum MSP-119 to MSP-8 will result in a chimeric vaccine that elicits potent, merozoite neutralizing immune responses that are superior to the responses induced by the current PfMSP-142 vaccines. The MSP-1/8 chimeric antigen is designed to provide strong, conserved, plasmodial-specific CD4+ T cell epitopes to promote the production of antibodies to protective B cell epitopes of MSP-1 and MSP-8, including those associated with the functionally related epidermal growth factor-like domains present in the two proteins. Specifically, we will design, produce and evaluate a PfMSP-1/8 chimeric vaccine that elicits high titers of antibodies that neutralize merozoites from diverse strains of P. falciparum. Testing will include a detailed analysis of i) T cell and B cell responses induced by immunization with the chimeric PfMSP-1/8 in comparison to PfMSP-119, PfMSP-142 or PfMSP-8 alone or an admixture of MSP-1 and MSP-8 components, ii) the ability to boost vaccine-induced immune responses by parasite associated antigen, and iii) the specificity of neutralizing antibodies for variant and/or conserved epitopes of PfMSP-1 and PfMSP-8. We have defined clear outcomes to measure 'enhancement'in immunogenicity and in merozoite neutralizing capacity. These studies will provide data to support the subsequent testing of this MSP-based P. falciparum vaccine in non-human primates and in human subjects. PUBLIC HEALTH RELEVANCE: The threat of disease and death due to Plasmodium falciparum malaria parasites continues unabated for nearly half of the world's population. This project is an effort to improve the immunogenicity and protective efficacy of P. falciparum MSP-1 based vaccines. Currently, P. falciparum MSP-1 is the leading blood-stage malaria vaccine candidate antigen.